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      Design, synthesis and pharmacological characterization of coumarin-based fluorescent analogs of excitatory amino acid transporter subtype 1 selective inhibitors, UCPH-101 and UCPH-102.

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          Abstract

          The excitatory amino acid transporters (EAATs) play a pivotal role in regulating the synaptic concentration of glutamate in the mammalian central nervous system. To date, five different subtypes have been identified, named EAAT15 in humans (and GLAST, GLT-1, EAAC1, EAAT4, and EAAT5, respectively, in rodents). Recently, we have published and presented a structure-activity relationship (SAR) study of a novel class of selective inhibitors of EAAT1 (and GLAST), with the analogs UCPH-101 (IC(50)=0.66μM) and UCPH-102 (IC(50)=0.43μM) being the most potent inhibitors in the series. In this paper, we present the design, synthesis and pharmacological evaluation of six coumarin-based fluorescent analogs of UCPH-101/102 as subtype-selective inhibitors at EAAT1. Analogs 1114 failed to inhibit EAAT1 function (IC(50) values >300μM), whereas analogs 15 and UCPH-102F inhibited EAAT1 with IC(50) values in the medium micromolar range (17μM and 14μM, respectively). Under physiological pH no fluorescence was observed for analog 15, while a bright blue fluorescence emission was observed for analog UCPH-102F. Regrettably, under confocal laser scanning microscopy selective visualization of expression of EAAT1 over EAAT3 was not possible due to nonspecific binding of UCPH-102F.

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          Author and article information

          Journal
          Bioorg Med Chem
          Bioorganic & medicinal chemistry
          Elsevier BV
          1464-3391
          0968-0896
          Dec 01 2012
          : 20
          : 23
          Affiliations
          [1 ] Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
          Article
          S0968-0896(12)00770-5
          10.1016/j.bmc.2012.09.049
          23072958
          fb6434a0-70e9-4d45-88b7-b2efde27fbde
          Copyright © 2012 Elsevier Ltd. All rights reserved.
          History

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